The present invention relates to a novel process for the preparation of 5-cyanophthalide which is an intermediate used in the manufacture of the well known antidepressant drug citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.
Citalopram is a well known antidepressant drug that has now been on the market for some years and has the following structure: 
It is a selective, centrally active serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities. The antidepressant activity of the compound has been reported in several publications, eg. J. Hyttel, Prog. Neuro-Psychopharmacol. and Biol. Psychiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75, 478-486.
Citalopram is prepared by the process described in U.S. Pat. No. 4,650,884, according to which 5-cyanophthalide is subjected to two successive Grignard reactions, i.e. with 4-fluoro-phenyl magnesium halogenide and N,N-dimethylaminopropyl magnesium halogenide, respectively, and the resulting compound of the formula 
is subjected to a ring closure reaction by dehydration with strong sulfuric acid.
Enantiomers of citalopram may be prepared by the method described in U.S. Pat. No. 4,943,590, i.e. by separating the enantiomers of the intermediate of Formula II and performing enantioselective ring closure in order to obtain the desired enantiomer.
Thus, 5-cyanophthalide is an important intermediate for the manufacture of citalopram and it is important to produce this material in an adequate quality, by a convenient process and in a cost-effective way.
A method for the preparation of 5-cyanophthalide has previously been described in Bull. Soc. Sci. Bretagne, 26, 1951, 35 and in Levy and Stephen, J. Chem. Soc., 1931, 867. By this method, 5-aminophthalide is converted to the corresponding 5-cyanophthalide by diazotation followed by reaction with CuCN. 5-Aminophthalide was obtained from 4-aminophthalimide by a two step reduction procedure.
Synthesis of certain alkyl- and phenylnitriles from acid chlorides is described in Tetrahedron Letters, 1982, 23, 14, 1505-1508, and in Tetrahedron, 1998, 54, 9281.
Though a number of other methods failed, it has been found that 5-cyanophthalide may be prepared in high yields by a convenient, cost-effective procedure from 5-carboxyphthalide.
Accordingly, the present invention provides a novel method for the preparation of 5-cyanophthalide from 5-carboxyphthalide comprising
a) converting 5-carboxyphthalide to an amide of Formula IV 
xe2x80x83in which R is hydrogen or C1-6 alkyl, and
b) then reacting the amide of Formula IV with a dehydrating agent thereby obtaining 5-cyanophthalide 
The conversion of 5-carboxyphthalide to the amide of Formula IV may be carried out via an ester of Formula VI or an acid chloride of Formula VII or via the ester and the acid chloride: 
wherein R1 is C1-6 alkyl or phenyl. The acid chloride is conveniently obtained by treatment of 5-carboxyphthalide with POCl3, PCl5 or SOCl2 neat or in a suitable solvent, such as toluene or toluene comprising a catalytic amount of N,N-dimethylformamide. The ester is obtained by treatment of 5-carboxyphthalide with an alcohol R1OH, wherein R1 is as defined above, in the presence of an acid, preferably a mineral acid or a Lewis acid, such as HCl, H2SO4, POCl3, PCl5 or SOCl2. Alternatively, the ester may be obtained from the acid chloride by reaction with an alcohol. The ester of Formula VI or the acid chloride of Formula VII is then converted to the amide of Formula IV by amidation with ammonia or an C1-6 alkylamine, preferably t-butyl amine.
Throughout the specification and Claims, C1-6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2,2-dimethyl-1-ethyl and 2-methyl-1-propyl.
The dehydrating agent used in step b) may be any suitable dehydrating agent, and the optimal agent may easily be determined by a person skilled in the art. Examples of suitable dehydrating agents are SOCl2, POCl3 and PCl5, preferably SOCl2.
The reaction in step b) is carried out neat or in a suitable solvent, such as toluene, sulfolan or conveniently acetonitrile. When the reaction is carried out in a solvent, 1.0-1.5, preferably 1.0-1.2 equivalents of dehydrating agent is used per equivalent of the amide of Formula V. Furthermore, when a solvent is used, a catalytic amount of N,N-dimethylformamide may be needed, in particular when the dehydrating agent is SOCl2. Preferably, toluene is used as the solvent, if necessary in the presence of a catalytic amount of N,N-dimethylformamide.
The reaction in step b) is carried out at elevated temperature, preferably at the reflux temperature of the solvent.
The reaction time is not important and may easily be determined by a person skilled in the art.
5-Cyanophthalide may be isolated in a conventional way, e.g. by addition of water, filtration and subsequent washing of the crystals. Further purification may, if desired, be performed by recrystallisation.
In a preferred embodiment of the process of the invention, R in Formula IV is H or t-butyl. When the reaction in step a) is carried out via an ester, R1 is preferably methyl or ethyl.
In a particularly preferred embodiment of the invention 5-carboxyphthalide of Formula III is reacted with an alcohol, R1OH, preferably ethanol, in the presence of POCl3, in order to obtain the corresponding ester of Formula VI, which is then reacted with ammonia thereby giving 5-carbamoylphthalide, which in turn is reacted with SOCl2 in toluene comprising a catalytic amount of N,N-dimethylformamide.
Surprisingly, substantially no reaction takes place at the lactone ring. Accordingly, by the process of the invention, 5-cyanophthalide is obtained in high yields and the process is much more convenient than the known process and uses more convenient and cheaper reactants and conditions.
The 5-carboxyphthalide used as a starting material may be obtained by the methods described in U.S. Pat. No. 3,607,884 or German patent No. 2630927, i.e. by reacting a concentrated solution of terephthalic acid with formaldehyde in liquid SO3 or by electrochemical hydrogenation of trimellithic acid.